To help us learn more about dealing with multidrug resistance, I contacted Dr. Eric Daar, the chief of HIV medicine at Harbor-UCLA Medical Center in Los Angeles and a professor of medicine at the David Geffen School of Medicine. He has been an active HIV physician and researcher since the 1980s, and is an authority on multidrug resistance.

Dr. Daar, I was wondering if you could tell me a little bit about what you do.

Sure. I'm a clinician scientist. I work at Harbor-UCLA Medical Center, where we take care of about 800 to 900 HIV-infected individuals in our clinic. We have largely a Ryan White-funded program, and take care of a very diverse patient population. We're dealing with many of the complexities of both [patients'] life and HIV disease. We have a very active research program -- primarily clinical research -- as well as research to better define how HIV actually causes disease. We study people, looking at novel ways to treat, or optimize therapy, as well as to further understand what's going on with the interaction between the person and the virus.

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How has the treatment of people who are treatment-experienced changed over the years? Are we in a new era now?

Yes. I don't think there's any question about it. Things have evolved over the last five years or so, and continue to evolve, particularly with the emergence of new drugs and new classes. We have, for a long time, realized that when people don't do well on their initial regimen that they can develop drug-resistant virus. In the early era of combination antiretroviral therapy, often that first regimen was the best shot at full suppression, and after that it became very difficult.

With new drugs, with new characteristics, we have had better success in people who have failed perhaps their first, or even second, regimen, with viral rebound. I think what we're finding now is that, even for people who are on their third, fourth or fifth regimen, we have a reasonable chance of achieving our goal, which has now evolved to being complete viral suppression -- even in these people who are more treatment experienced with multidrug-resistant virus.

Management of the Treatment-Experienced Patient

These guidelines come from the January 29, 2008 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents -- a working group of the Office of AIDS Research Advisory Council (OARAC)

Panel's Recommendations:

In treatment-experienced patients with suppressed viremia, assess adherence frequently and simplify the regimen as much as possible. Change individual antiretroviral drugs to reduce or manage toxicity, as needed.

Evaluation of antiretroviral treatment failure in a patient should include an assessment of the severity of HIV disease of the patient; the antiretroviral treatment history, including the duration, drugs used, antiretroviral potency, adherence history, and drug intolerance/toxicity; HIV RNA and CD4 T-cell count trends over
time; and the results of prior drug resistance testing.

Virologic failure on treatment can be defined as a confirmed HIV RNA level >400 copies/mL after 24 weeks, >50 copies/mL after 48 weeks, or a repeated detectable HIV RNA level after prior suppression of viremia.

Drug resistance testing should be obtained while the patient is taking the failing antiretroviral regimen (or within 4 weeks of treatment discontinuation).

The goal of treatment for patients with prior drug exposure and drug resistance is to reestablish maximal virologic suppression, HIV RNA <50 copies/mL.

Use the treatment history and the past and current resistance test results to identify fully active agents to design a new regimen. A fully active agent is one that is likely to have antiretroviral activity on the basis of both the treatment history and susceptibility on drug resistance testing. Adding at least 2 (preferably
3) fully active agents to an optimized background antiretroviral regimen can provide significant antiretroviral activity.

Immunologic failure can be defined as a failure to achieve and maintain an adequate CD4 response despite virologic suppression.

For immunologic failure, current medications, untreated coinfection, and serious medical conditions should be assessed.

There is no consensus for when and how to treat immunologic failure.

Assessing and managing a patient who has antiretroviral experience, who exhibits drug resistance, and who is experiencing treatment failure is complex and expert advice is critical.

Could we define treatment-experienced? If someone has a resistance test and they're resistant to almost everything, does that mean that they're now a treatment-experienced or rescue patient? What if someone only took one or two regimens; does that mean that they are suddenly in that category of "treatment experienced"?

Yes. Really, at least when I talk about somebody being treatment experienced, I'm thinking of the person who, for any one of a variety of reasons, has had difficulties with their first, early regimens, whether that's because they've experienced viral rebound with drug-resistant virus, or because they've not tolerated existing agents; I think of them as treatment experienced.

"... we don't just look at the results from the current resistance test right now; we'll also want to go back and look through the patient's medical record and perhaps look at previous drug resistance tests to further define what kinds of resistant virus they'd selected for in the past."

Then, from the perspective of resistance, we can further characterize them as having limited treatment options, being highly drug resistant -- or, perhaps, those who have a lot of options, because they don't have a lot of resistance but maybe have had some difficulties with their earlier regimens because of tolerability, or their ability to take the medications consistently.

So we really hate to put everybody in the same group, and we're thinking about a range of individuals who have been on treatment in the past and are looking at subsequent regimens, some of whom have many options as far as available treatments, and others who are more limited.

In terms of dealing with a resistance test that shows that someone is resistant to everything, what are the first things that you do?

One of the more complicated situations is in people who have a lot of drug resistance. The current guidelines have recommended for the last year or so, that our goal still be to see if we can come up with a new regimen that would allow them to have complete viral suppression, or get their viral loads to levels that are undetectable. The reason we do that is partly because, obviously, we think they'll do better. But even more importantly, it's because we believe if we can do that, we can prevent their virus from becoming resistant to the new drugs, as well. That's why it's our goal.

I'll preface this by saying that, while that is our goal, it's not always achievable in everybody. It's not to suggest that if you can't achieve that goal right now, all is lost -- because that's clearly not the case. It just means that we need to redefine the goals and be strategic.

Let me tell you how we work through a patient like this, who comes to us, who has perhaps been on therapy in the past and has experienced viral rebound on that treatment. The first thing we'll do is that we'll try to get a sense as to which group they fall within. Are they the kind of person who is treatment experienced, with minimal drug-resistant virus, or a lot of drug resistance? You mentioned a patient who has the more extensive resistance pattern. But it can really be everything in between.

We'll look at their drug resistance, usually with a drug resistance test, whether it be a genotype or a phenotype -- but one of these tests that can be performed in the clinic and will give us the sense as to which drugs their virus may still be susceptible to.

In addition (and this is extremely important), we don't just look at the results from the current resistance test; we'll also want to go back and look through the patient's medical record and perhaps look at previous drug resistance tests to further define what kinds of resistant virus they'd selected for in the past. We'll also look at their treatment history. Sometimes that will give us clues as to which drugs may or may not be active.

So then it's really important that patients keep a copy of their medical records.

It's extremely important that patients keep a copy of their records, particularly in the current era, where people do move around a lot, or their insurance changes and forces them to seek out medical care in another environment. So as proactive as the patient can be in making sure that they have access to all their medical records, the better since it will assist their new provider in coming up with the best regimen.

Could you define viral rebound?

Yes. Viral rebound: What we're talking about in the most obvious case is somebody whose viral load went to undetectable, or below the limits of detection with the current assays [tests]. Then, while they're taking treatment, suddenly it's noted that their virus rebounds, or comes back up to detectable levels. We realize that sometimes that can happen at low levels, and it's meaningless. You simply repeat the results and it's back down to undetectable, in which case there's no problem. But in the people where it's persistently detectable, we think they have had viral rebound.

That can occur for a variety of reasons. The obvious one, and the one we're focusing on is that the person has actually developed resistance to their drugs. But there are other times where that may not be true. It may be because they are simply not taking their medications consistently.

"If you don't achieve that goal of getting an undetectable viral load -- that is our optimal goal -- then it's inevitable that some resistance or increasing resistance will occur."

Is HIV drug resistance always a consequence of someone not taking their meds?

No. Resistance can occur for a lot of reasons. One of the big risk factors for it occurring is not taking the medications consistently. But it can also occur if the regimen that's selected is not sufficiently potent or doesn't have enough active drugs within the regimen to get the virus down to undetectable. If you don't achieve that goal of getting an undetectable viral load -- that is our optimal goal -- then it's inevitable that some resistance or increasing resistance will occur.

Walk me through this. If someone has an undetectable viral load and they get the results of their most recent viral load test and their viral load is now detectable, how quickly should something be done? What should be done? Is it at that point that a drug resistance test should be taken?

I think the first step is to make sure the person's taking the medications consistently. This requires a very open dialogue between the patient and the provider. Because we really want our patients to feel comfortable sharing with us any problems they are having with taking their medications. This is a group effort. This isn't something that needs to be left to the patient alone. If they are having difficulties, whether it's because the medications make them sick, or the way the medications are given -- is it a bad time of the day for them, around their work or schedule, or other factors -- or if the person is using drugs, or depressed, or binge drinking on the weekends and missing their doses. The best thing that the patient can do is share that with their provider, so that we can work together to figure out what to do next to try to avoid the development of resistance.

So that's the first step. The next step is to make sure that that rebound in virus is consistent. So we'll generally repeat the test. I don't think there's any urgency -- meaning, days or minutes -- but over the next week, or month, these things need to be sorted out so a decision can be made as to whether to do a drug resistance test, and then how, or if, to modify therapy based upon those results.

So what's the timeline for all this? Let's say I get back a viral load test that is detectable. Then am I immediately given another test? Or do you wait a week or so?

I don't think there are hard and fast rules. I wouldn't wait three months. But I think, over the next week or several weeks or a month, depending on convenience for the patient, I don't think a lot is going to change over that period of time. But you don't want it to go on much longer than three to six weeks.

So you get another viral load test. If that test shows that you're still detectable, then is that the point when a resistance test is given?

Yes. I think that would be the right time [to give another resistance test]. There are some caveats. In people whose viral loads are low -- for example, less than maybe 1,000 -- there can be difficulties in doing drug resistance testing. So sometimes they need to be followed more closely, or occasionally decisions need to be made on changing therapy without resistance testing. That requires a more detailed discussion.

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